Regulation of lipid metabolism by PPARalpha (Homo sapiens)
From WikiPathways
Description
Peroxisome proliferator-activated receptor alpha (PPAR-alpha) is the major regulator of fatty acid oxidation in the liver. PPARalpha is also the target of fibrate drugs used to treat abnormal plasma lipid levels.
PPAR-alpha is a type II nuclear receptor (its subcellular location does not depend on ligand binding). PPAR-alpha forms heterodimers with Retinoid X receptor alpha (RXR-alpha), another type II nuclear receptor. PPAR-alpha is activated by binding fatty acid ligands, especially polyunsaturated fatty acids having 18-22 carbon groups and 2-6 double bonds.
The PPAR-alpha:RXR-alpha heterodimer binds peroxisome proliferator receptor elements (PPREs) in and around target genes. Binding of fatty acids and synthetic ligands causes a conformational change in PPAR-alpha such that it releases the corepressors and binds coactivators (CBP-SRC-HAT complex, ASC complex, and TRAP-Mediator complex) which initiate transcription of the target genes.
Target genes of PPAR-alpha participate in fatty acid transport, fatty acid oxidation, triglyceride clearance, lipoprotein production, and cholesterol homeostasis. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=400206
PPAR-alpha is a type II nuclear receptor (its subcellular location does not depend on ligand binding). PPAR-alpha forms heterodimers with Retinoid X receptor alpha (RXR-alpha), another type II nuclear receptor. PPAR-alpha is activated by binding fatty acid ligands, especially polyunsaturated fatty acids having 18-22 carbon groups and 2-6 double bonds.
The PPAR-alpha:RXR-alpha heterodimer binds peroxisome proliferator receptor elements (PPREs) in and around target genes. Binding of fatty acids and synthetic ligands causes a conformational change in PPAR-alpha such that it releases the corepressors and binds coactivators (CBP-SRC-HAT complex, ASC complex, and TRAP-Mediator complex) which initiate transcription of the target genes.
Target genes of PPAR-alpha participate in fatty acid transport, fatty acid oxidation, triglyceride clearance, lipoprotein production, and cholesterol homeostasis. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=400206
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Bibliography
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History
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External references
DataNodes
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Annotated Interactions
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Source | Target | Type | Database reference | Comment |
---|---|---|---|---|
ALAS1 gene
NRF1 PPARGC1B | Arrow | REACT_115949 (Reactome) | ||
Coactivators of PPARalpha | REACT_19175 (Reactome) | |||
Corepressors of PPARalpha | Arrow | REACT_19175 (Reactome) | ||
Corepressors of PPARalpha | REACT_19283 (Reactome) | |||
ESRRA | Arrow | REACT_115949 (Reactome) | ||
FABP1 Ligands of PPARA | REACT_19175 (Reactome) | |||
FABP1 | Arrow | REACT_19175 (Reactome) | ||
NR1D1 | TBar | REACT_116112 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115533 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115542 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115547 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115550 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115593 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115624 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115625 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115631 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115644 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115677 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115721 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115729 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115739 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115770 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115777 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115807 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115815 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115847 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115875 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115878 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115879 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115927 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115945 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115949 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115953 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115962 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115967 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115978 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115979 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115994 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_115997 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_116020 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_116040 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_116079 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_116112 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_116133 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_116136 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_116159 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_116163 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_19175 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_25084 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_27168 (Reactome) | ||
PPARA RXRA Coactivator Complex | Arrow | REACT_27173 (Reactome) | ||
PPARA RXRA Heterodimer | REACT_19283 (Reactome) | |||
PPARA RXRA Repressor Complex | REACT_19175 (Reactome) | |||
PPARA | REACT_19370 (Reactome) | |||
PPARG
Fatty Acid RXRA Mediator Coactivator Complex | Arrow | REACT_27168 (Reactome) | ||
PPARG
Fatty Acid RXRA Mediator Coactivator Complex | Arrow | REACT_27173 (Reactome) | ||
Peroxisome Proliferator Receptor Element | REACT_19370 (Reactome) | |||
REACT_115533 (Reactome) | The GLIPR1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115542 (Reactome) | The Adipophilin (PLIN2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115547 (Reactome) | The CYP4A11 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115550 (Reactome) | The CYP7A1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115593 (Reactome) | The TIAM2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115624 (Reactome) | The ACOX1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115625 (Reactome) | The RGL1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115631 (Reactome) | The APOA5 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115644 (Reactome) | The CPT1A gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115677 (Reactome) | The TXNRD1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115721 (Reactome) | The FABP1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115729 (Reactome) | The SULT2A1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115739 (Reactome) | The HMGCS1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115770 (Reactome) | The GRHL1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115777 (Reactome) | The UGT1A9 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115807 (Reactome) | The ABCB4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115815 (Reactome) | The TRIB3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115847 (Reactome) | The ME1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115875 (Reactome) | The TNFRSF21 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115878 (Reactome) | The ANKRD1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115879 (Reactome) | The AGT gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115927 (Reactome) | The CPT2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115945 (Reactome) | The FDFT1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115949 (Reactome) | The ALAS1 gene is transcribed to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. The ALAS1 precursor is imported into the mitochodrial matrix where it catalyzes the synthesis of 5-aminolevulinate from glycine and succinyl-CoA as part of heme biosynthesis. | |||
REACT_115953 (Reactome) | The FADS1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115962 (Reactome) | The PEX11A gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115967 (Reactome) | The G0S2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115978 (Reactome) | The ACSL1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115979 (Reactome) | The FATP1 (SLC27A1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115994 (Reactome) | The ABCA1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_115997 (Reactome) | The HMGCR gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_116020 (Reactome) | The ACADM gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_116040 (Reactome) | The FHL2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_116079 (Reactome) | The CYP1A1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_116112 (Reactome) | The NPAS2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of NPAS2 is enhanced by the RORA:Coactivator complex and repressed by the REV-ERBA:Corepressor complex. | |||
REACT_116133 (Reactome) | The APOA2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_116136 (Reactome) | The HMGCS2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_116159 (Reactome) | The APOA1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
REACT_116163 (Reactome) | The CTGF gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of the CTGF gene is increased by both YAP1:TEAD and WWTR1(TAZ):TEAD transcriptional coactivator:transcription factor complexes, so that CTFG is one of the many genes whose expression is downregulated by the action of the hippo cascade (Zhang et al. 2009; Zhao et al. 2008). | |||
REACT_19175 (Reactome) | PPAR-alpha is activated by binding polyunsaturated fatty acids especially those having 18-22 carbon groups and 2-6 double bonds. These ligands bind the C-terminal region of PPAR-alpha and include linoleic acid, linolenic acids, arachidonic acid, and eicosapentaenoic acid. The fibrate drugs are also agonists of PPAR-alpha. Binding of a ligand causes a conformational change in PPAR-alpha so that it recruits coactivators. By analogy with the closely related receptor PPAR-gamma, PPAR-alpha probably binds TBL1 and TBLR1, which are responsible for recruiting the 19S proteasome to degrade corepressors during the exchange of corepressors for coactivators. The coactivators belong to the CBP-SRC-HAT complex (CBP/p300, SRC1, SRC2, SRC3, CARM1, SWI/SNF, BAF60C, PRIC320, and PRIC285), the ASC complex (PRIP/ASC2, PIMT), and the TRAP-DRIP-ARC-MEDIATOR complex (TRAP130, PBP/TRAP220). The coactivators contain LXXLL motifs (Nuclear Receptor Boxes) that interact with the AF-2 region in nuclear receptors such as PPAR-alpha. | |||
REACT_19283 (Reactome) | In the absence of activating ligands of PPAR-alpha, the PPAR-alpha:RXR-alpha heterodimers recruit corepressors NCoR1, NCoR2(SMRT), and histone deacetylases (HDACs) to genes regulated by PPAR-alpha. The corepressors maintain chromatin at the gene in an inactive conformation and prevent expression of the gene. | |||
REACT_19370 (Reactome) | Peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a type II nuclear receptor (its subcellular location is independent of ligand binding) related to PPAR-beta/delta and PPAR-gamma. PPAR-alpha is expressed highly in the liver where if functions to control lipid metabolism, especially fatty acid oxidation. PPAR-alpha forms heterodimers with Retinoid X receptor alpha (RXR-alpha). The heterodimers bind peroxisome proliferator receptor elements (PPREs) in and around genes regulated by PPAR-alpha. | |||
REACT_25084 (Reactome) | The PPARA gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, BMAL1:CLOCK heterodimers bind the scond intron of the PPARA gene and activate transcription of PPARA. | |||
REACT_27168 (Reactome) | The Platelet glycoprotein IV gene (CD36, PAS IV, GPIV) is transcribed to yield mRNA and the mRNA is translated to yield proteind. | |||
REACT_27173 (Reactome) | The ANGPTL4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. | |||
ROR-alpha Coactivator | Arrow | REACT_115644 (Reactome) | ||
ROR-alpha Coactivator | Arrow | REACT_116112 (Reactome) | ||
RXRA | REACT_19370 (Reactome) | |||
SREBP1A/1C/2
NF-Y HMGCS1 gene | Arrow | REACT_115739 (Reactome) | ||
SREBP1A/1C/2
NF-Y SP1 FDFT1 gene | Arrow | REACT_115945 (Reactome) | ||
SREBP1A/2
NF-Y HMGCR gene | Arrow | REACT_115997 (Reactome) | ||
TBL1XR1 | REACT_19283 (Reactome) | |||
TBL1X | REACT_19283 (Reactome) | |||
TEAD WWTR1 | Arrow | REACT_116163 (Reactome) | ||
TEAD YAP1 | Arrow | REACT_116163 (Reactome) | ||
p-BMAL1
p-CLOCK/NPAS2 DNA | Arrow | REACT_25084 (Reactome) |